Phylogenetic relationships among organisms have been demonstrated many times, and studies from a diversity of prokaryotic and eukaryotic organisms suggest a more or less gradual evolution of biochemical and physiological mechanisms and metabolic pathways. Despite different evolutionary pressures, proteins that regulate the cell cycle in yeast, nematode, fly, rat, and man have common chemical or structural features and modulate the same general activity. Comparisons of human gene sequences with those from other organisms where structure and/or function are known allow researchers to draw analogies and to develop model systems for testing hypotheses. These model systems are of great importance in developing and testing diagnostic and therapeutic agents for human conditions, diseases, and disorders.
The phospholipid transfer protein family, important in phospholipid trafficking, includes phosphatidylinositol transfer protein (PI-TP, identical to yeast SEC 14p), non-specific lipid transfer protein (nsL-TP, identical to sterol carrier protein 2), and phosphatidylcholine transfer protein (PC-TP). The sequence of PC-TP is unique and unrelated to other cytosolic lipid transfer proteins. It is encoded by a single gene and appears to be present in all eukaryotes (Geijtenbeek et al. (1996) Biochem J 316:49-55). Although amino acid compositions, molecular weights, and elution profiles of bovine and porcine PC-TP differ markedly, they retain similar transfer activity levels suggesting that amino acid composition of PC-TP can be altered without changing activity and specificity (Chen et al. (1991) Biochem Int 23:377-382).
PC-TP catalyzes PC intermembrane transfer (Feng and Cohen (1998) J Lipid Res 39:1862-1869), and certain PC molecular species are secreted preferentially into bile. Using multivariate analysis, LaMorte et al. (1998; Hepatology 28:631-637) examined the relationship between PC structure and the probability that individual PC species are secreted into the bile. They suggest that the likelihood of a PC being secreted into bile is closely related to its binding affinity for PC-TP.
Bovine liver PC-TP binds one molecule of PC non-covalently. Bound PC is not the predominant molecular species representative of bovine liver. Although PC species carrying a palmitoyl chain at the sn-1 position are abundant in bovine liver, they are rarely found bound as PC-TP. These findings led Geijtenbeek et al. (1996; FEBS Lett 391:333-335) to suggest that PC-TP may have a role in the metabolism of highly unsaturated, stearoyl-containing PC molecular species.
PC is implicated in many different diseases relating to phospholipid metabolism, including neutral lipid storage disease (NLSD), lung diseases such as atelectasis, edema, and cystic fibrosis, and cholecystitis (Nicholas (1996) Respirology 1:247-257; Griese et al. (1997) Eur Respir J 10:1983-1988; and Venkataramani et al. (1998) Am J Gastroenterol 93:434-441). NLSD is a genetic disorder causing abnormalities in the regulation of phospholipid metabolism. Igal and Coleman (1998; J Lipid Res 39:31-43) suggest that an underlying regulatory defect in NLSD alters the rates of synthesis and degradation of the major cellular phospholipids including phosphatidylcholine and phosphatidyletha-nolamine.
Phosphatidylinositol-transfer proteins are important in vesicle-trafficking and signal-transduction (Cockcroft (1998) Bioessays 20:423-432; Alb et al. (1996) Curr Opin Cell Biol 8:534-541). Because PC-TP is a member of the family containing PI-TP, catalyzes PC intermembrane transfer (Feng and Cohen, supra), and is found in many organs (lung, kidney, testis, liver, etc.); PC is implicated in vesicle trafficking disorders and transport disorders. Therefore, the ability to control PC-TP provides the ability to intercede in disease processes.
The discovery of a nucleic acid molecule encoding a phospholipid transfer protein provides new compositions which are useful in the characterization, diagnosis, and treatment of disorders associated with cell proliferation, lipid metabolism and transport.